# Molecular mechanisms of memory consolidation in the medial prefrontal cortex

> **NIH NIH F31** · NEW YORK UNIVERSITY · 2020 · $39,190

## Abstract

Project Summary
The hippocampal memory system processes episodic and semantic memory, containing information about
who, what, where and when, that are critical in contextualizing experiences to form memories. Cellular
consolidation mechanisms in long-term memory have been well studied within the hippocampus using rodent
models, uncovering regulation of immediate early genes and target effectors required for synaptic plasticity.
The systems consolidation hypothesis posits that the hippocampus, however, becomes disengaged over time,
identifying cortical regions, including the medial prefrontal cortex (mPFC), as a putative site of long term
memory processing and storage. This redistribution process can take up to years in humans, but in rat models
of contextual fear memories takes about 2-4 weeks. The molecular mechanisms that enable the mPFC to
process and store memories across this extended time frame are unknown. The Alberini lab has recently
uncovered novel mechanisms in the prelimbic (PL) subregion of the mPFC in rats in a related cognitive
process, memory reconsolidation, wherein memory recall can result in memory enhancement. Specifically,
postsynaptic cell adhesion molecules neuroligin 1 (NLGN1) and NLGN2, isolated to excitatory and inhibitory
synapses, respectively, simultaneously support memory strengthening while also suppressing memory
extinction. These data inform the overarching hypothesis of this proposal that NLGN1 and NLGN2 play a
critical role in long term memory consolidation by balancing excitatory and inhibitory synapses in the PL cortex
with experience. Research from other laboratories indicates that learning-dependent disinhibition of fast-
spiking parvalbumin-positive interneurons (PVINs) in the PL cortex synchronize excitatory cell output and is
crucial for fear memory expression. Moreover, Nlgn2 knockout in mice preferentially degrades PVIN
neurotransmission but spares other inhibitory neuron subtypes. Taken together, I propose that fear memory
consolidation requires experience dependent NLGN2 regulation on PVINs in the PL cortex to create a
disinhibitory circuit that regulates excitatory neuron output, in part mediated by NLGN1 regulation. I will test this
hypothesis using biochemical and behavioral techniques, with a particular interest in NLGN2 on PVINs as a
disinhibitory mechanism. Aim 1 will determine the temporal profile of NLGN1 and NLGN2 protein regulation
following learning, and subsequently block their function in vivo to test whether they are required for long term
memory. Aim 2 will measure learning-induced NLGN1 and NLGN2 changes on individual neuron types, and
then knockout Nlgn2 in PVINs in the PL cortex using a novel cre-dependent CRISPR-Cas9 approach in PV-cre
rats to determine an effect on long term memory formation and maintenance. These results will provide a
proposed molecular substrate for PL mechanisms of systems consolidation. Memory deficits are shared
among many neuropsychiatric diseases; therefore...

## Key facts

- **NIH application ID:** 9988915
- **Project number:** 5F31MH116585-03
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Aaron C Katzman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,190
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988915

## Citation

> US National Institutes of Health, RePORTER application 9988915, Molecular mechanisms of memory consolidation in the medial prefrontal cortex (5F31MH116585-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9988915. Licensed CC0.

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